Regenerative medicine and tissue engineering have emerged as some of the most fascinating fields with potentially high clinical applications. If an adult human unfortunately loses a digit or limb, the wounds heal without signs of regeneration. Among amniotes, some lizards show a remarkable ability to regenerate tails following amputation. Here we propose to develop this unique in vivo model of regeneration to understand the unique molecular/ cellular mechanisms underlying repair and regeneration. The long term goal is to learn how animals do this process in Nature and to be able to apply these principles to benefit regeneration and bio-engineering following human amputation (e.g., limb, digit). Examples of ideal animal models that helped to improve our understanding of physiological and pathological phenomena include the use of Drosophila, C. elegans, etc. A unique phenomenon in reptiles is "autotomy" in which the stressed lizards automatically break their tails at specific fracture planes. Regeneration then initiates from these planes. Since this becomes part of the "physiological" process, we hypothesize that stem cells may reside in niches located near the facture plane, similar to bulge stem cells in hair molting cycles. Alternatively, cells in wounds may undergo de- differentiation to generate pluri-potential blastema. In either case, the regeneration is initiated and tissue morphogenesis progresses beyond simple repair. To test for these possibilities, we will pursue the following aims. 1) Characterize the regenerative events following wounding of reptile tails, including cell proliferation, apoptosis and migration. 2) Locate the origin of precursor cells in regenerating reptile tails, including the use of long-term label retention and chromatin status markers. 3) What molecular events are involved during reptile tail regeneration? Development related signaling molecule pathways (e.g., Msx, beta catenin, Shh, BMP, FGF, etc.) will be prioritized for mapping studies. Likely candidates will be perturbed using electroporation of siRNA. [unreadable] [unreadable] [unreadable] [unreadable]